A young woman with fever and polyserositis caused by familial Mediterranean fever

A younger lady with fever and polyserositis brought on by familial Mediterranean fever


  • Familial Mediterranean fever (FMF) is the most typical monogenic autoinflammatory dysfunction; it’s characterised by self-limited episodes of fever, polyserositis, and elevated inflammatory markers.

  • Whereas signs are nonspecific, FMF needs to be suspected in sufferers with recurrent febrile episodes accompanied by peritonitis, pleuritis, pericarditis, and elevated C-reactive protein, particularly amongst folks of Ashkenazi Jewish descent and different at-risk ethnic teams.

  • Therapy with colchicine prevents medical flare-ups and amyloidosis and renal failure that could be related to the illness.

  • Delayed prognosis can have severe penalties for sufferers, together with pointless operations and related problems.

In 2015, a 28-year-old lady of Ashkenazi Jewish descent introduced to the medical genetics clinic with issues about versatile joints, straightforward bruising, stretchy pores and skin, power again ache, and delicate scoliosis since childhood. Differential diagnoses included connective tissue issues equivalent to EhlersDanlos (EDS), Marfan and LoeysDietz syndromes. She had an elevated Beighton rating (6/9), reflecting joint hypermobility and not one of the options in step with Marfan syndrome or LoeysDietz syndrome. Her echocardiogram was regular and her household historical past was unremarkable. A panel of 13 genes was unfavourable for EDS and she or he was given a medical prognosis of hypermobile EDS.

Over the subsequent 5 years, the affected person developed recurrent episodes of fever, elevated C-reactive protein (CRP), stomach ache, and different signs (Desk 1). Though most episodes lasted 13 days, the affected person typically famous recurrence or worsening of post-procedure signs, equivalent to fever or stomach ache after varied surgical procedures.

Desk 1:

Chronology of occasions for a 28-year-old lady with familial Mediterranean fever

In 2016, the affected person underwent an ovarian cystectomy for suspected ovarian torsion (no torsion discovered), an appendectomy for suspected appendicitis (no appendicitis discovered), and an endoscopic retrograde cholangiopancreatography with stent placement for suspected power pancreatitis. In 2017, she obtained diagnoses of cholecystitis, power pancreatitis, and malnutrition, resulting in a cholecystectomy and central line placement for complete parenteral vitamin. She additionally had chest ache and shortness of breath with pleural effusions; suspected volvulus, which led to emergency laparotomy, with no proof of volvulus intraoperatively; and thrombophlebitis within the inner jugular vein. Intermittent stomach ache, distention, and nausea have been attributed to colonic dysmotility associated to hypermobile EDS. She was severely malnourished and her physique mass index dropped from 20.3 to fifteen.8, resulting in placement of a gastrojejunostomy tube to help enteral vitamin and keep away from problems related to long-term complete parenteral vitamin.

The sufferers’ medical standing worsened all through 2018 with flare-ups of stomach ache, constipation and feeding intolerance, which continued to be attributed to colonic dysmotility secondary to hypermobile EDS. Gram-negative enteric micro organism have been recognized on blood cultures twice and have been attributed to the impact of her EDS on the integrity of the intestinal wall, resulting in bacterial translocation. Whole colectomy and ileostomy have been carried out, adopted by extended restoration, with recurrent fever, elevated CRP, and stomach ache. After a interval of stability, reversal of her ileostomy with J-pouch formation was sophisticated by postoperative stomach ache, fever, and elevated CRP. In 2019, she had episodes of left decrease quadrant ache and tenesmus, recognized as pouchitis and handled with antibiotics. In 2020, the affected person had episodes of pelvic ache and fever lasting 23 days, elevated inflammatory markers, pericardial effusion, hepatosplenomegaly, and blood cultures optimistic for Escherichia coli. She was recognized with urosepsis and prescribed antibiotics.

In 2020, the affected person sought a genetic reassessment. No medical prognosis was made; nonetheless, it was believed that her historical past couldn’t be defined by hypermobile EDS. A geneticist ordered complete exome sequencing, which discovered compound heterozygous pathogenic DNA variants within the MEFV gene, specifically c.2084A>G (p.Lys695Arg) and c.2177T>C (p.Val726Ala), in step with familial Mediterranean fever (FMF).

The affected person was referred to a rheumatologist and began on colchicine 0.6 mg as soon as day by day. Within the 2 years since she started taking colchicine, she has had 2 delicate, self-resolving flares of FMF that didn’t require hospitalization or intervention. She has returned to her baseline energy and dietary standing and has stopped all different drugs. She has no proof of renal amyloidosis; her serum creatinine (71 mmol/L) and urea (4.4 mmol/L) are inside the regular vary, and she or he has no protein within the urine.


Familial Mediterranean fever is the most typical monogenic autoinflammatory dysfunction; it’s characterised by self-limiting episodes of fever, polyserositis and elevated inflammatory markers.14 The situation is related to gain-of-function sequence variations i MEFV gene that codes for the pyrin protein, leading to uncontrolled manufacturing of interleukin-1 and an exaggerated inflammatory response.1,2,4 The illness manifests as repeated assaults of fever, stomach ache and chest ache, which begin abruptly and peak shortly after onset, final for 14 days after which disappear spontaneously. Sufferers usually don’t have any signs between assaults.2 Familial Mediterranean fever needs to be thought-about for sufferers who’ve undergone laparotomy or laparoscopy with out recognized pathology. Stress, publicity to chilly, high-fat meals, infections, vigorous train, surgical procedure and the menstrual cycle can all set off an assault. Familial Mediterranean fever could current uncommonly as erysipelas-like erythema, aseptic meningitis, recurrent urticaria, or vasculitis.3

Laboratory abnormalities throughout assaults are nonspecific and embrace elevated systemic markers of irritation, leukocytosis with neutrophilia, and elevated erythrocyte sedimentation fee, CRP, and fibrinogen. Serum amyloid A protein can also be elevated throughout assaults however will not be routinely measured except a prognosis of FMF is suspected.3 One of many long-term problems of untreated illness is renal amyloidosis, which has been reported to be current in approx. . % of sufferers with FMF; it might probably have severe problems, together with kidney failure. 1,2 Amyloidosis may also develop within the spleen, liver, gastrointestinal tract, thyroid gland and testes. Small bowel obstruction could develop as a consequence of recurrent peritonitis and adhesion formation. Earlier than colchicine was used to deal with FMF, infertility was frequent and regarded as brought on by obstruction of the fallopian tubes in ladies and testicular amyloidosis in males.2,3

Familial Mediterranean fever is frequent in folks of Ashkenazi Jewish descent, with a big provider fee (about 1:7,8).5 The incidence is about 1 in 500 to 1 in 1,000 amongst folks of different ethnically at-risk origins, together with these of Turkish, Armenian, Arab, non-Ashkenazi Jewish, North African, Italian, Greek, Chinese language, and Japanese descent. Identified danger components embrace household historical past of FMF, which is current in 30%–50% of individuals with the situation and belonging to an ethnic danger group.6 Greater than 95% of genetic carriers are asymptomatic; nonetheless, some people with a single mutation could present signs and should profit from remedy with colchicine.1

Our sufferers’ many episodes of fever and stomach ache led to totally different diagnoses, invasive procedures and problems. Intraoperative findings and postoperative pathology studies have been typically inconsistent with the preliminary prognosis of hypermobile EDS, and hospital stays have been extended as a consequence of postoperative flares of ache, fever, and elevated CRP. In the course of the course of her sickness, treating clinicians didn’t appear to have thought-about FMF.

Hypermobile EDS is the mildest subtype of EDS, with out life-threatening problems, though sufferers with hypermobile EDS could have several types of gastroesophageal dysmotility equivalent to esophageal dysmotility, gastroparesis, small bowel or colonic transit time alteration, or world dysmotility. the vascular EDS subtype, hypermobile EDS doesn’t trigger bowel wall fragility or rupture. Genes for hypermobile EDS haven’t but been recognized. Vascular EDS and different EDS subtypes have been extremely unlikely on this affected person, given her unfavourable outcomes from genetic testing. Hypermobile EDS wouldn’t clarify the affected person’s signs, besides maybe colonic dysmotility.7

After the affected person developed new signs in 2015, genetics specialists weren’t consulted once more till the affected person requested a follow-up in 2020. She certified for whole-genome sequencing based mostly on Ontario Ministry of Well being testing standards for extreme impairment, multisystem involvement, and progressive medical course. When FMF or one other periodic fever syndrome is suspected, a periodic fever syndrome gene panel can determine pathogenic DNA variants. When variants of unknown medical significance or single pathogenic DNA variants are discovered, a prognosis can nonetheless be made based mostly on medical findings utilizing diagnostic standards such because the Eurofever-PRINTO classification standards.1,8 Entire-genome sequencing could also be helpful in sufferers with extreme multisystem involvement, even within the absence of a transparent prognosis. A affected person may also have greater than 1 genetic dysfunction, as in our affected person with FMF and hypermobile EDS.

Most sufferers with FMF are symptomatic by the age of 20.4 Looking back, the affected person had fever with extreme stomach ache a number of instances a yr, beginning in early childhood. Familial Mediterranean fever needs to be thought-about in a differential for recurrent fever, peritonitis and elevated CRP (Desk 2).

Desk 2:

Differential prognosis for sufferers with intermittent fever and elevated inflammatory markers

Therapy with colchicine is efficient, stopping FMF flare-ups in additional than 60% of sufferers and lowering the variety of assaults in one other 20%-30% of sufferers. Colchicine may also stop the deposition of amyloid fibrils and subsequent kidney failure.24,7,9 Antiinterleukin-1 biologic remedy can be utilized in sufferers unresponsive to colchicine.24

The signs of FMF can mimic different situations, and sadly, sufferers with FMF typically expertise years of misdiagnosis, pointless surgical procedures and extended hospitalizations. 4,6,10 Delays in prognosis most likely happen as a consequence of lack of specificity in signs and the recurrent and remitting sample of illness. Moreover, clinicians could not think about the illness in at-risk ethnic populations.4

The Instances part presents quick case studies that convey clear, sensible experiences. Choice is given to frequent displays of necessary uncommon situations and necessary uncommon displays of frequent issues. Articles begin with a case presentation (max 500 phrases) and a dialogue of the underlying situation follows (max 1000 phrases). Visible parts (eg tables of the differential prognosis, medical options or diagnostic method) are inspired. Consent from sufferers to the publication of their historical past is a necessity. See data for authors at www.cmaj.ca.


  • Competing pursuits: None declared.

  • This text has been peer reviewed.

  • The authors have obtained the affected person’s consent.

  • Contributors: All authors contributed to the conception and design of the article. Kayla Richard and Sara Glazer drafted the primary model of the manuscript and contributed equally. All authors revised the manuscript critically for necessary mental content material, gave remaining approval of the model to be printed, and agreed to be chargeable for all facets of the work.

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